1. Field of the Invention
The present invention relates to substituted indole, azaindole and tetrahydro-1H-pyrrolo[2,3-c]pyridin-7-one compounds and derivatives thereof, useful as angiotensin II antagonists, particularly effective in the control of smooth and cardiac muscle contraction, especially for the treatment of cardiovascular disorders such as hypertension and congestive heart failure. Additionally, the compounds of the present invention are useful for the treatment of chronic renal failure, cognitive and affective disorders, and disorders of the alimentary tract.
2. Related Disclosures
The renin-angiotensin system is a fundamental physiological mechanism for regulating blood pressure in mammals. Angiotensinogen is secreted into the bloodstream by the liver. Angiotensinogen is then cleaved by the protease renin to yield the decapeptide angiotensin I, which in turn is hydrolyzed by angiotensin converting enzyme (ACE) to the octapeptide angiotensin II. Angiotensin I is inactive in the cardiovascular system, but angiotensin II has numerous cardiovascular-renal activities. For example, it stimulates the adrenal cortex to secrete aldosterone, which causes the kidneys to retain sodium and water, increasing blood pressure. It causes vasoconstriction. It also facilitates neurotransmission in the sympathetic nervous system.
The effects of angiotensin II, such as arteriolar vasoconstriction, contraction of gastro-intestinal smooth muscle, aldosterone secretion, glycogenolysis, alteration of renal function and CNS effects, are mediated by the activation of specific angiotensin II receptors on smooth and cardiac muscle, adrenal medulla, brain, liver and kidney. Angiotensin II receptors are categorized into subtypes, for example the AT-1 and AT-2 subtypes. It is evident that disease states associated with activation of angiotensin II receptors could be usefully treated by compounds possessing angiotensin II antagonist activity.
Various angiotensin II receptor antagonists are known. See, for example, U.S. Pat. Nos. 4,333,943, 4,880,804, 5,053,329, and European Patents 0 245 637, 0 253 310, and 0 291 969, and also Wong et al., Hypertension 15:459 (1990), J. Pharmacol. Exp. Ther. 256:211 (1990), and Chiu et al., Biochem. Biophys. Res. Comm. 165:196-203 (1989).